Anticancer effect evaluation in vitro and in vivo of iridium(III) polypyridyl complexes targeting DNA and mitochondria

Bioorg Chem. 2021 Oct:115:105290. doi: 10.1016/j.bioorg.2021.105290. Epub 2021 Aug 19.

Abstract

To investigate the antitumor effect of iridium complexes, three iridium (III) complexes [Ir(ppy)2(dcdppz)]PF6 (ppy = 2-phenylpyridine, dcdppz = 11,12-dichlorodipyrido[3,2-a:2',3'-c]phenazine) (Ir1), [Ir(bzq)2(dcdppz)]PF6 (bzq = benzo[h]quinoline) (Ir2) and [Ir(piq)2(dcdppz)]PF6 (piq = 1-phenylisoquinoline) (Ir3) were synthesized and characterized. Geometry optimization, molecular dynamics simulation and docking studies have been performed to further explore the antitumor mechanism. The cytotoxicity of Ir1-3 toward cancer cells was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The localization of complexes Ir1-3 in the mitochondria, intracellular accumulation of reactive oxygen species (ROS) levels, the changes of mitochondrial membrane potential and morphological changes in apoptosis were investigated. Flow cytometry was applied to quantify fluorescence intensity and determine cell cycle distribution. Western blotting was used to detect the expression of apoptosis-related proteins. The anti-tumor effect of Ir1 in vivo was evaluated. The results showed that Ir1-3 had high cytotoxicity to most tumor cells, especially to SGC-7901 cells with a low IC50 value. Ir1-3 can increase the intracellular ROS levels, reduce the mitochondrial membrane potential. Additionally, the complexes induce an increase of apoptosis-related protein expression, enhance the percentage of apoptosis. The complexes inhibit the cell proliferation at G0/G1 phase. The results obtained from antitumor in vivo indicate that Ir1 can significantly inhibit the growth of tumors with an inhibitory rate of 54.08%. The docking studies show that complexes Ir1-3 interact with DNA through minor-groove intercalation, which increases the distance of DNA base pairs, leading to a change of DNA helix structure. These experimental and theoretical findings indicate that complexes Ir1-3 can induce apoptosis in SGC-7901 cells through the mitochondrial dysfunction and DNA damage pathways, and then exerting anti-tumor activity in vitro and vivo.

Keywords: Antitumor; Iridium(III) complex; Mitochondrial damage; Molecular dynamics simulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • DNA, Neoplasm / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Iridium / chemistry
  • Iridium / pharmacology*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Molecular Structure
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • DNA, Neoplasm
  • Pyridines
  • Reactive Oxygen Species
  • Iridium